Biology of Sex Differences最新文献

Background: The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to rising obesity rates. Maternal obesity (MO) is associated with increased susceptibility to metabolic disorders, including MASLD, in the offspring. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a hallmark of heterochromatin, plays a vital role in development by silencing gene programs dispensable for differentiated cell types. This study investigated how MO influences gene expression and chromatin architecture in male and female offspring liver, in early postnatal live and upon sexual maturity.

Methods: Female mice were fed a Western-style diet or a control diet before and throughout pregnancy and lactation. The offspring were weaned at 3 weeks and subsequently transitioned to a standard chow diet for 5 weeks.

Results: At 3 weeks, the liver transcriptomes of control offspring were similar between sexes. However, MO disrupted hepatic gene expression in both sexes, leading to the dysregulation of hundreds of genes and alterations in H3K9me3 binding patterns. By 8 weeks, as the mice reached sexual maturity, control offspring showed considerable sex-based gene expression divergence, with over 1,800 genes showing differential expression. These genes were predominantly involved in immune response regulation, cell adhesion and extracellular matrix organization, xenobiotic and glutathione-mediated detoxification, cholesterol metabolism, and lipid partitioning. Furthermore, thousands of differentially bound H3K9me3 peaks were observed between the 3- and 8-week time points. A significant fraction of these peaks were located on the X chromosome in females, suggesting a role in X inactivation. Remarkably, MO offspring displayed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes by week 8, underscoring the long-term impact of maternal diet on the genomic and metabolic landscape.

Conclusions: Collectively, this study highlights inherent sex differences in liver gene expression, and suggests that H3K9me3 plays a role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by 5 weeks of postnatal dietary normalization.

Background: βeta-2 glycoprotein I (β2GPI, Apolipoprotein H) is a plasma glycoprotein best known as a major autoantigen in autoimmune disorders such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), both of which confer elevated cardiovascular risk. Despite its prominence in autoimmunity, its role in lipid metabolism and potential sex-specific effects remain poorly understood.

Methods: We investigated β2GPI's influence on lipoprotein profiles using β2GPI knockout (KO) and wild-type (WT) mice subjected to normal chow (NC) and high-fat (HF) diets, as well as plasma from β2GPI-deficient patients and aged and sex matched controls. Lipoprotein fractions were analyzed for cholesterol and apolipoprotein content, and protein interactions were assessed by co-immunoprecipitation.

Results: In animal studies, female β2GPI KO mice-but not males-displayed significantly increased total plasma cholesterol on a HF diet and greater cholesterol content within HDL fractions. Apo E was enriched in HDL fractions from female KO mice under both NC and HF diets, and plasma Apo E was elevated in HF-fed female KOs. In WT females on HF diet, β2GPI was enriched in HDL fractions, and β2GPI co-immunoprecipitated with Apo E. In human studies, the β2GPI-deficient female patient exhibited increased HDL cholesterol, a shift toward larger HDL particles, and enriched Apo E in HDL fractions relative to controls. Co-immunoprecipitation confirmed β2GPI-Apo E interaction in human plasma, with binding requiring Domain V of β2GPI.

Conclusions: Our findings identify β2GPI as a sex-specific regulator of HDL metabolism. In females, β2GPI modulates Apo E-containing HDL particles, influencing cholesterol distribution and lipoprotein composition. These results reveal a novel mechanism linking β2GPI to lipid homeostasis, with potential implications for cardiovascular risk in women with autoimmune disease. Targeting β2GPI-Apo E interactions may represent a therapeutic avenue for correcting dysregulated HDL metabolism in female-specific cardiometabolic and autoimmune contexts.

Background: Genotypic (GSD) and environmental (ESD) sex determination coexist in many species of reptiles, fish, and amphibians. Inherited genotypic signals and environmental factors conceivably interact as pro-testis or pro-ovary signals during sex determination, but how such interactions affect gonadal sex differentiation in these species remains largely unexplained. This study uses a model gonochoristic fish with coexisting GSD and ESD, the pejerrey Odontesthes bonariensis, to examine how synergism and antagonism between sex genotype (XX/XY) and thermal (feminizing/masculinizing) regimes interactively affect environmental sensitiveness and the critical time of environmental sex determination as well as how genotype-by-environment conflicts are resolved.

Methods: We performed a series of controlled rearing experiments involving shift-once and shift-twice transfers of fish of known sex genotype (XX/XY) between feminizing and masculinizing temperatures at different stages of gonadal sex differentiation. Match/mismatch analysis of phenotypic (ovary/testis) and genotypic (absence/presence of the master sex determining gene amhy) sex was performed in juveniles to estimate sex reversal rates and the critical period of sex determination for each combination of sex genotype and thermal conditions.

Results: The results show that convergence/divergence between genotypic and environmental signals advances/delays the critical time of sex determination and lowers/raises the degree of environmental sensitiveness, respectively, even when genotypic control is ultimately overridden. This study also provides evidence that ovarian formation is the default state regardless of genotypic sex but commitment to femaleness is a lengthy, passive process requiring absolute seclusion from environmental pro-male stimuli in the span of weeks. Testis formation, in turn, is the alternative state that can be imposed on this default, regardless of genotype, by an extremely short (range of hours) environmental stimulus of sufficient strength at any time before ovarian commitment. We argue that this combination of developmental features increases the likelihood of male development and at the same time may be crucial to avoid ambiguous differentiation under conflicting genotypic/environmental signals in GSD + ESD species.

Conclusions: Overall, the results reveal genotypic sex-dimorphic critical periods of sex determination, show that it is "easier" to make males in pejerrey, and provide clues to understand how GSD + ESD species may prevent discrepant sex determination/differentiation when genotype and environment diverge.

Background: The phrase "Throwing like a girl" persists in popular culture and in scientific research as a trope about biological differences between males and females. In this review/theoretical paper I critically examine the support for the idea that sex differences in throwing style and force result from innate biological difference.

Methods: This article contains (1) a limited critical review of selected literature, (2) the application of a systems approach to the development of ball play that starts the study of throwing capacity as it develops in infancy and considers its emergence going forward and (3) a demonstration of this approach using qualitative descriptions of events (at ages 9-15 months) involving toddlers' first engagements in ball play.

Results: The literature cited to support the claim that sex differences in throwing are a ubiquitous/universal feature of human children is weak. When I compared two toddlers over several months, starting at the time of their first ball throwing game, I learned that the boy and his mother played frequently even before he could walk. In contrast, the girl began ball play at an older age that coincided with her learning to walk. For 8 additional children, the boys started playing ball almost 2.5 months earlier than the girls, and all before they could walk.

Conclusions: The boy could raise the ball higher and throw it further at 13-14 months because he had practiced more from the more stable sitting and kneeling positions which allowed him to master double-handed overhead ball throwing before he could walk. The girl tried throwing the ball while walking unsteadily. Thus, when trying to raise the ball above her head, she often fell, and could not throw it very far. I conclude that to understand sex differences in embodied motor skills in children requires that we study the processes of motor learning beginning at birth.

Background: Females have been underrepresented in preclinical and clinical research. Research on females is important for conditions that directly affect women, disproportionately impact women, and manifest differently in women. Sex and gender mandates were introduced, in part, to increase women's health research. This study aimed to understand how much of women's health research is being funded in open grant competitions in Canada that fall under the top burden and/or death of disease for women globally.

Methods: Publicly available funded Canadian Institute of Health Research (CIHR) project grant abstracts from 2009 to 2023 were coded for the mention of female-specific research to assess what percentage of grant abstracts focused on the top 11 areas of global disease burden and/or death that disproportionately affect females. We also examined changes from 2020 to 2023 in the representation of grant abstracts that mentioned sex, gender, or two-spirit, lesbian, gay, bisexual, trans, queer, intersex (2S/LGBTQI).

Results: The percentage of abstracts mentioning sex or gender doubled whereas the percentage of abstracts mentioning 2S/LGBTQI quadrupled from 2020 to 2023, but remained at under 10% of overall funded abstracts. In contrast, female-specific research representation remained at ~ 7% of all research. Under 5% of the total funded grant abstracts mentioned studying one of the top 11 global burdens of disease and/or death for women over 15 years. Of the 681 female-specific grants, cancer research accounted for 35% of funding (or 2.25% of overall grants), whereas the other top 10 collectively accounted for 37% of female-specific funding (or 2.35% overall) across 15 years. The percentage of overall funding towards understanding female-specific contributions to cardiovascular disease was 0.70% followed by diabetes (0.34%), HIV/AIDS (0.54%), depression (0.32%), anxiety (0.17%), musculoskeletal disorders (0.13%), dementia (0.09%), respiratory disorders (0.06%), headache disorders (0.002%) and low back pain (0.01%).

Conclusions: Research acknowledging the sex and gender population in CIHR abstracts is increasing but remains at under 10% while the percentage of funding for women's health remains unchanged at 7% of funded grants across 15 years.

Background: Men have consistently experienced higher COVID-19 mortality than women across most countries and time periods, prompting widespread investigation into potential biological causes. Early research focused on sex-related genetic, hormonal, and immunological mechanisms to explain these disparities.

Main body: This narrative review traces the evolution of scientific explanations for women/men mortality differences in COVID-19, from early biological hypotheses to more nuanced gendered and intersectional models. While some studies suggest sex-linked genetic variants, chromosomal mechanisms, or hormone-regulated expression of viral entry receptors might partially explain men's higher mortality, the overall evidence remains inconsistent and inconclusive. Increasingly, attention has shifted to social and structural factors, including occupational exposure, pre-existing health conditions, healthcare access, and behaviors, that can differently shape vulnerability to COVID-19 in women and men. Data disaggregated by gender and race further revealed significant heterogeneity in outcomes, underscoring the influence of intersecting axes of inequality. International comparisons suggested that gender inequality at the societal level was associated with wider women/men COVID-19 mortality gaps. Analyses that overlook the interaction between sex- and gender-related factors and their intersection with racial disparities and socioeconomic status risk obscuring the underlying drivers of COVID-19 disparities.

Conclusion: Sex-related biological factors may have influenced COVID-19 outcomes, but they do not adequately account for the observed differences in mortality between women and men. Approaching the study of health inequities through a gendered, intersectional framework is essential for accurately identifying and addressing underlying risk factors, and for better understanding how sex- and gender-related factors may interact, not only in COVID-19, but across a broad range of health conditions.

Background: The circadian system influences many different biological processes across the lifespan, including memory performance and daily activity patterns. The biological process of aging causes decreased control of the circadian system that is accompanied by a decline in memory performance, suggesting that these two processes may be linked. Indeed, our previous work has shown that in male mice, the clock gene Per1 functions within the dorsal hippocampus to exert diurnal control over memory and repression of Per1 in the old hippocampus contributes to age-related impairments in spatial memory. Although it is clear that Per1 may be a key molecular link between memory and the circadian rhythm, next to nothing is known about how sex impacts this role in the young or old brain. Here, we are interested in understanding how the factors of sex and age impact memory performance, circadian activity patterns, sleep behavior, and hippocampal Per1 expression.

Methods: We used a combination of spatial memory (Object Location Memory (OLM)) and circadian activity monitoring to determine how male and female mice change across the lifespan. In addition, we used RT-qPCR to quantify the change in Per1 levels in response to learning in young and old, male and female mice.

Results: Young female mice resist diurnal oscillations in memory, showing robust spatial memory across the diurnal cycle. In contrast, old female mice show an emergence of diurnal memory oscillations, with better memory during the day than at night (similar to what we observed previously in young male mice). In contrast, old male mice showed better memory performance during the night than the day, suggesting that their peak memory performance is drastically shifted compared to young males. We also measured activity patterns and sleep behavior across the diurnal cycle and found that sex was more of an influence than age in multiple analyses, but age did have an impact, with old male mice showing stronger circadian rhythm disruptions than any other cohort. Finally, we investigated whether the circadian clock gene Per1 plays a role in these sex- and age-dependent effects in diurnal memory performance. We found that, in general, learning-induced Per1 and memory performance peaked at similar times of day in each group, consistent with our hypothesis that Per1 exerts diurnal control over memory performance.

Conclusions: This work supports a role for Per1 in exerting diurnal control over memory and suggests that Per1 may be an appealing therapeutic target to improve memory and circadian dysfunction in old age.

Highlights: Diurnal oscillations in spatial memory are sex- and age-dependent in mice. Per1 learning-induced expression matches diurnal memory patterns. Circadian rhythm patterns are sex- and age-dependent in mice. Young females show good memory across the diurnal cycle. Diurnal memory o

Background: RAW 264.7 (male-derived) and J774A.1 (female-derived) cell lines are widely used in immunology research and are considered preferred models for studying signaling pathways, yet their responses to gonadal hormones remain poorly understood. Gonadal hormones, particularly estrogen, shape immune cell function and contribute to sex differences in disease outcomes, with macrophages playing a central role through their expression of intracellular estrogen receptors (ERs). Herein, we investigated ER expression and functional responses to 17β-estradiol (E2) in male-derived RAW 264.7 and female-derived J774A.1 macrophages, in 2D culture. Additionally, we looked at sex-matched and mismatched media conditions in a 3D hydrogel system. Our results reveal distinct phenotypic and functional differences between the cell lines, emphasizing the need for sex-aware approaches in immunological research and model design.

Methods: RAW 264.7 and J774A.1 macrophages were cultured in basal media for 24 hours, then treated with varying concentrations of 17β-estradiol (5, 25, 100 nM), as well as hormone-free and control media. Post-treatment analyses included viability, estrogen receptor expression, phenotype skewing, matrix metalloprotease 9 (MMP9) activity, and phagocytosis. These macrophages were also used to condition sex-specific media environments and were encapsulated in a hydrogel network containing adhesive and cleavable sites. Encapsulated cells were then exposed to sex-matched or sex-mismatched conditioned media, and proliferation and MMP9 activity were assessed.

Results: Our results revealed distinct differences in estrogen receptor gene and protein expression, as well as in core macrophage functions such as proliferation, inflammation, matrix remodeling, and phenotype skewing. Additionally, the sex-derivation of the surrounding molecular environment affected macrophage behavior in a 3D hydrogel system. Female-derived macrophages were more sensitive in terms of proliferation to sex-mismatched environments, while male-derived macrophages exhibited altered enzyme activity when exposed to female-conditioned media.

Conclusions: These findings underscore the importance of accounting for both the origin of immune cells as well as the hormonal and environmental context in which they are studied. Without these considerations, experimental models risk missing critical biological differences that shape immune responses and disease outcomes.

Background: Sex is an important factor in the development and symptom expression of Parkinson's disease (PD). Risk of developing PD, motor and non-motor symptoms and response to treatment differ between men and women, with women showing lower disease incidence, later onset of motor deficits and generally milder symptoms than men. We previously reported that male mice lacking the NF-κB/c-Rel protein (c-rel^-/- mice) undergo age-related accumulation of α-synuclein, and loss of dopaminergic neurons, in the substantia nigra (SN). In addition, c-rel^-/- male mice present a progressive PD-like phenotype characterized by both motor deficits and non-motor symptoms (such as constipation, hyposmia, anxiety, depressive-like behavior and apathy). In this study, we give evidence that female mice reproduce only part of the parkinsonian pathology and do not show behavioral manifestations.

Methods: Nigro-striatal alterations as well as motor and non-motor symptoms were assessed in aged c-rel^-/- and wild-type (wt) male and female mice through histological techniques and behavioral tests.

Results: Likewise c-rel^-/- males, c-rel^-/- females displayed significant reduction of dopaminergic neurons in the SN at 18 months of age, but only minor reduction of striatal TH-positive (TH+) and DAT-positive (DAT+) dopaminergic fibers compared to wt littermates. Besides, c-rel^-/- females did not develop significant motor deficits and non-motor symptoms, as constipation, hyposmia, depressive-like and apathetic behaviors.

Conclusions: Our results show that, differently from aged males, c-rel^-/- females do not develop a parkinsonian behavior, in line with evidence from the human PD. The phenotype mice display a nigral dopaminergic neuron degeneration but conserved nigrostriatal fiber density. The degeneration and PD-like symptoms are compatible with the sex-related differences on incidence and symptoms progression observed in PD patients.

Males are more susceptible to neurodevelopmental cognitive deficits in their perception of visual information. Subliminally-presented visual stimuli might be subconsciously perceived and consequently influence upcoming decisions, however it is still unclear whether subconscious perception differs between males and females. In this study, young adults performed a two-choice target detection task. In the Baseline condition (trials), participants relied only on their ability to detect the target. In the Cued-conscious condition, a visual cue (information) was presented (250 ms) on the same side of an upcoming target and indicated its location (left/right). In the Subliminal-same condition, a briefly presented (~16 ms) cue correctly indicated the target location, however in the Subliminal-opposite condition the cue was shown on the opposite side of the upcoming target and provided incorrect information. Participants' performance in the Cued-conscious condition was significantly higher than the Baseline and subliminal conditions. In both females and males, performance in the Subliminal-same and Subliminal-opposite conditions was higher and lower than the Baseline condition respectively; indicating that the subliminal cues (information) affected upcoming decisions. However, the effects were significantly larger in males, suggesting males express heightened sensitivity to subliminal visual information, compared to age- and education-matched females. In both males and females, background acoustic stimuli (Music, White noise or Silence) influenced conscious and subconscious visual information processing. Autonomic nervous system activity, assessed through event-related electrodermal activity, was also differentially modulated by supraliminal and subliminal visual information. Our findings indicate remarkable sex dependency in the effects of subliminal visual information on cognitive functions.